tbuckley/cabot-search huggingface dataset:
Perioperative Atezolizumab Plus Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel for Resectable Esophagogastric Cancer: Interim Results From the Randomized, Multicenter, Phase II/III DANTE/IKF-s633 Trial
Authors: Sylvie Lorenzen, Thorsten Oliver Götze, Peter Thuss-Patience, Matthias Biebl, Nils Homann, Michael Schenk, Udo Lindig, Vera Heuer, Albrecht Kretzschmar, Eray Goekkurt, Georg Martin Haag, Jorge Riera-Knorrenschild, Claus Bolling, Ralf-Dieter Hofheinz, Tianzuo Zhan, Stefan Angermeier, Thomas Jens Ettrich, Alexander Reinhard Siebenhuener, Moustafa Elshafei, Wolf Otto Bechstein, Timo Gaiser, Maria Loose, Disorn Sookthai, Christina Kopp, Claudia Pauligk, Salah-Eddin Al-Batran
Journal: Journal of Clinical Oncology (2023)

This trial evaluates the addition of the PD-L1 antibody atezolizumab (ATZ) to standard-of-care fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) as a perioperative treatment for patients with resectable esophagogastric adenocarcinoma (EGA).
Olaparib for the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer and Alterations in <i>BRCA1</i> and/or <i>BRCA2</i> in the PROfound Trial
Authors: Joaquin Mateo, Johann S. de Bono, Karim Fizazi, Fred Saad, Neal Shore, Shahneen Sandhu, Kim N. Chi, Neeraj Agarwal, David Olmos, Antoine Thiery-Vuillemin, Mustafa Özgüroğlu, Niven Mehra, Nobuaki Matsubara, Jae Young Joung, Charles Padua, Ernesto Korbenfeld, Jinyu Kang, Helen Marshall, Zhongwu Lai, Alan Barnicle, Christian Poehlein, Natalia Lukashchuk, Maha Hussain
Journal: Journal of Clinical Oncology (2023)

Olaparib improved PFS and OS across subgroups of BRCA1/2mut #prostatecancer patients in the PROFOUND phase III trial.
Convergent MAPK pathway alterations mediate acquired resistance to FGFR inhibitors in FGFR2 fusion-positive cholangiocarcinoma
Authors: Timothy P. DiPeri, Ming Zhao, Kurt W. Evans, Kaushik Varadarajan, Tyler Moss, Stephen Scott, Michael P. Kahle, Charnel C. Byrnes, Huiqin Chen, Sunyoung S. Lee, Abdel-Baset Halim, Hiroshi Hirai, Volker Wacheck, Lawrence N. Kwong, Jordi Rodon, Milind Javle, Funda Meric-Bernstam
Journal: Journal of Hepatology (2023)
Neoadjuvant Immunotherapy in Gastroesophageal Cancer: A Promising Early Signal?
Authors: Mojun Zhu, Harry H. Yoon
Journal: Journal of Clinical Oncology (2023)

In the article that accompanies this editorial, Lorenzen et al 1 report exploratory efficacy findings, focused on pathologic response, of neoadjuvant immunotherapy-containing chemotherapy in patients with resectable gastric/gastroesophageal junction (GEJ) adenocarcinoma (GEA) in the ongoing DANTE/FLOT8 trial.DANTE is an open-label phase II/III trial (German AIO) in which patients are randomly assigned to receive pre-/post-operative FLOT with atezolizumab versus FLOT alone.To our knowledge, the current article is the first full manuscript, to date, to report efficacy results from a randomized controlled trial (RCT) evaluating the addition of immunotherapy to chemotherapy in the neoadjuvant setting for this disease.The most noteworthy finding is a higher pathologic complete response (pCR) rate in the immunotherapy-containing arm.6][7] Together, these promising results raise the possibility that neoadjuvant immunotherapy-containing treatment in GEA might improve survival, thereby helping address the fourth-highest cause of cancer mortality in the world. 8r resectable disease, a current standard treatment for adenocarcinomas of the stomach/GEJ is perioperative FLOT. 9For adenocarcinomas of the esophagus, a common treatment is neoadjuvant chemoradiation (CRT) followed by surgery and, if residual pathologic disease exists, adjuvant nivolumab. 10,11Regrettably, <60% of patients are alive 3 years later with either approach. 9,12,13e primary end point of DANTE in the original phase II design (N 5 295) was progression-/ disease-free survival (DFS); then, on the basis of encouraging results from immunotherapy trials for advanced-stage disease, the trial was converted to a phase III trial (N 5 556) with a primary end point of event-free survival (EFS).The primary end point of the phase II portion was subsequently modified to surgical pathology response (eg, pCR), with the original phase II end points modified to be exploratory or secondary.The current manuscript reports these surgical pathology data from the phase II portion.Notably, the pCR rate was higher in the atezolizumab-containing arm versus control (eg, ypT0N0 23% v 14%).Differences persisted even when patients who were mismatch repair-deficient (dMMR) were excluded.No new safety signals were identified.
Outcomes and characteristics of nonmelanoma skin cancers in patients with myeloproliferative neoplasms on ruxolitinib
Authors: Alex Rampotas, Luke Carter-Brzezinski, Tim C. P. Somervaille, James Forryan, Fotios Panitsas, Claire Harrison, Ruth Witherall, Andrew J. Innes, Louise Wallis, Naumann M. Butt, Bethan Psaila, Adam J. Mead, Matthew Carter, Anna L. Godfrey, Heather Laing, Mamta Garg, Sebastian Francis, Joanne Ewing, Chun Huat Teh, Hannah Bibi Cowen, Peter Dyer, Conall McConville, Frances Wadelin, Ali Sahra, Andrew McGregor, Elizabeth Kulakov, Donal P. McLornan, Jonathan Lambert
Journal: Blood (2023)
Lineage Plasticity: The New Cancer Hallmark on the Block
Authors: Arnav Mehta, Ben Z. Stanger
Journal: Cancer Research (2023)

Plasticity refers to the ability of cells to adopt a spectrum of states or phenotypes. In cancer, it is a critical contributor to tumor initiation, progression, invasiveness, and therapy resistance, and it has recently been recognized as an emerging cancer hallmark. Plasticity can occur as a result of cell-intrinsic factors (e.g., genetic, transcriptional, or epigenetic fluctuations), or through cell-extrinsic cues (e.g., signaling from components of the tumor microenvironment or selective pressure from therapy). Over the past decade, technological advances, analysis of patient samples, and studies in mouse model systems have led to a deeper understanding of how such plastic states come about. In this review, we discuss: (i) the definition of plasticity; (ii) methods to measure and quantify plasticity; (iii) the clinical relevance of plasticity; and (iv) therapeutic hypotheses to modulate plasticity in the clinic.
Oligodendrocyte progenitor cells in Alzheimer’s disease: from physiology to pathology
Authors: Peibin Zou, Chongyun Wu, Timon Cheng-Yi Liu, Rui Duan, Luodan Yang
Journal: Translational Neurodegeneration (2023)

Abstract Oligodendrocyte progenitor cells (OPCs) play pivotal roles in myelin formation and phagocytosis, communicating with neighboring cells and contributing to the integrity of the blood–brain barrier (BBB). However, under the pathological circumstances of Alzheimer’s disease (AD), the brain’s microenvironment undergoes detrimental changes that significantly impact OPCs and their functions. Starting with OPC functions, we delve into the transformation of OPCs to myelin-producing oligodendrocytes, the intricate signaling interactions with other cells in the central nervous system (CNS), and the fascinating process of phagocytosis, which influences the function of OPCs and affects CNS homeostasis. Moreover, we discuss the essential role of OPCs in BBB formation and highlight the critical contribution of OPCs in forming CNS-protective barriers. In the context of AD, the deterioration of the local microenvironment in the brain is discussed, mainly focusing on neuroinflammation, oxidative stress, and the accumulation of toxic proteins. The detrimental changes disturb the delicate balance in the brain, impacting the regenerative capacity of OPCs and compromising myelin integrity. Under pathological conditions, OPCs experience significant alterations in migration and proliferation, leading to impaired differentiation and a reduced ability to produce mature oligodendrocytes. Moreover, myelin degeneration and formation become increasingly active in AD, contributing to progressive neurodegeneration. Finally, we summarize the current therapeutic approaches targeting OPCs in AD. Strategies to revitalize OPC senescence, modulate signaling pathways to enhance OPC differentiation, and explore other potential therapeutic avenues are promising in alleviating the impact of AD on OPCs and CNS function. In conclusion, this review highlights the indispensable role of OPCs in CNS function and their involvement in the pathogenesis of AD. The intricate interplay between OPCs and the AD brain microenvironment underscores the complexity of neurodegenerative diseases. Insights from studying OPCs under pathological conditions provide a foundation for innovative therapeutic strategies targeting OPCs and fostering neurodegeneration. Future research will advance our understanding and management of neurodegenerative diseases, ultimately offering hope for effective treatments and improved quality of life for those affected by AD and related disorders.
CircMMP2(6,7) Cooperates with β-Catenin and PRMT5 to Disrupt Bone Homeostasis and Promote Breast Cancer Bone Metastasis
Authors: Yingru Xu, Xincheng Li, Shuxia Zhang, Miaoling Tang, Ruyuan Yu, Xinyi Liao, Ziwen Li, Man Li, Suwen Chen, Wanying Qian, Libing Song, Zunfu Ke, Jun Li
Journal: Cancer Research (2023)

Abstract The bone is the most common site of distant metastasis of breast cancer, which leads to serious skeletal complications and mortality. Understanding the mechanisms underlying breast cancer bone metastasis would provide potential strategies for the prevention and treatment of breast cancer bone metastasis. In this study, we identified a circular RNA that we named circMMP2(6,7) that was significantly upregulated in bone metastatic breast cancer tissues and correlated with breast cancer–bone metastasis. Upregulation of circMMP2(6,7) dramatically enhanced the metastatic capability of breast cancer cells to the bone via inducing bone metastatic niche formation by disrupting bone homeostasis. Mechanistically, circMMP2(6,7) specifically bound to the promoters of bone-remodeling factors calcium-binding protein S100A4 and carbohydrate-binding protein LGALS3 and formed a complex with β-catenin and arginine methyltransferase PRMT5, eliciting histone H3R2me1/H3R2me2s-induced transcriptional activation. Treatment with GSK591, a selective PRMT5 inhibitor, effectively inhibited circMMP2(6,7)/β-catenin/PRMT5 complex–induced breast cancer bone metastasis. These findings reveal a role for circMMP2(6,7) in bone homeostasis disruption and shed light on the mechanisms driving breast cancer bone metastasis. Significance: Upregulation of bone-remodeling factors S100A4 and LGALS3 mediated by a circMMP2(6,7)/β-catenin/PRMT5 complex generates a niche that supports breast cancer bone metastasis, identifying PRMT5 as a promising target for treating metastasis.
Walking the tightrope between DNA damage repair and genomic integrity
Authors: Matthew K Summers, Monica Venere
Journal: Neuro-Oncology (2023)

Journal Article Walking the tightrope between DNA damage repair and genomic integrity Get access Matthew K Summers, Matthew K Summers Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, Ohio, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Monica Venere Monica Venere Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, Ohio, USA Corresponding Author: Monica Venere, PhD, Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH 43017, USA (Monica.Venere@osumc.edu) https://orcid.org/0000-0001-6498-3390 Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, Volume 26, Issue 3, March 2024, Pages 399–400, https://doi.org/10.1093/neuonc/noad218 Published: 14 November 2023 Article history Published: 14 November 2023 Corrected and typeset: 05 December 2023
RNA Methyltransferase FTSJ3 Regulates the Type I Interferon Pathway to Promote Hepatocellular Carcinoma Immune Evasion
Authors: Qiuyu Zhuang, Zhiguo Dai, Xuechun Xu, Shaoyi Bai, Yindan Zhang, Youshi Zheng, Xiaohua Xing, En Hu, Yingchao Wang, Wuhua Guo, Bixing Zhao, Yongyi Zeng, Xiaolong Liu
Journal: Cancer Research (2023)

Immunotherapies such as immune checkpoint blockade have achieved remarkable success in treating cancer. Unfortunately, response rates have been limited in multiple cancers including hepatocellular carcinoma (HCC). The critical function of epigenetics in tumor immune evasion and antitumor immunity supports harnessing epigenetic regulators as a potential strategy to enhance the efficacy of immunotherapy. Here, we discovered a tumor-promoting function of FTSJ3, an RNA 2'-O-methyltransferase, in HCC by suppressing antitumor immune responses. FTSJ3 was upregulated in hepatocellular carcinoma, and high FTSJ3 expression correlated with reduced patient survival. Deletion of FTSJ3 blocked HCC growth and induced robust antitumor immune responses. Mechanistically, FTSJ3 suppressed double-stranded RNA (dsRNA)-induced IFNβ signaling in a 2'-O-methyltransferase manner. Deletion of RNA sensors in HCC cells or systemic knockout of type I IFN receptor IFNAR in mice rescued the in vivo tumor growth defect caused by FTSJ3 deficiency, indicating that FTSJ3 deletion suppresses tumor growth by activating the RNA sensor-mediated type I IFN pathway. Furthermore, FTSJ3 deletion significantly enhanced the efficacy of programmed cell death protein 1 (PD-1) immune checkpoint blockade. The combination of FTSJ3 deficiency and anti-PD-1 antibody treatment effectively eradicated tumors and increased the survival time. In conclusion, this study reveals an epigenetic mechanism of tumor immune evasion and, importantly, suggests FTSJ3-targeting therapies as potential approach to overcome immunotherapy resistance in patients with HCC.
Small Cell Lung Cancer Plasticity Enables NFIB-Independent Metastasis
Authors: Julie H. Ko, Kyle E. Lambert, Debadrita Bhattacharya, Myung Chang Lee, Caterina I. Colón, Haley Hauser, Julien Sage
Journal: Cancer Research (2023)

Metastasis is a major cause of morbidity and mortality in patients with cancer, highlighting the need to identify improved treatment and prevention strategies. Previous observations in preclinical models and tumors from patients with small cell lung cancer (SCLC), a fatal form of lung cancer with high metastatic potential, identified the transcription factor NFIB as a driver of tumor growth and metastasis. However, investigation into the requirement for NFIB activity for tumor growth and metastasis in relevant in vivo models is needed to establish NFIB as a therapeutic target. Here, using conditional gene knockout strategies in genetically engineered mouse models of SCLC, we found that upregulation of NFIB contributes to tumor progression, but NFIB is not required for metastasis. Molecular studies in NFIB wild-type and knockout tumors identified the pioneer transcription factors FOXA1/2 as candidate drivers of metastatic progression. Thus, while NFIB upregulation is a frequent event in SCLC during tumor progression, SCLC tumors can employ NFIB-independent mechanisms for metastasis, further highlighting the plasticity of these tumors.
Neuronal Activity Promotes Glioma Progression by Inducing Proneural-to-Mesenchymal Transition in Glioma Stem Cells
Authors: Xiaofan Guo, Wei Qiu, Chaochao Wang, Yanhua Qi, Boyan Li, Shaobo Wang, Rongrong Zhao, Bo Cheng, Xiao Han, Hao Du, Zijie Gao, Ziwen Pan, Shulin Zhao, Gang Li, Hao Xue
Journal: Cancer Research (2023)

Abstract Neuronal activity can drive progression of high-grade glioma by mediating mitogen production and neuron-glioma synaptic communications. Glioma stem cells (GSC) also play a significant role in progression, therapy resistance, and recurrence in glioma, which implicates potential cross-talk between neuronal activity and GSC biology. Here, we manipulated neuronal activity using chemogenetics in vitro and in vivo to study how it influences GSCs. Neuronal activity supported glioblastoma (GBM) progression and radioresistance through exosome-induced proneural-to-mesenchymal transition (PMT) of GSCs. Molecularly, neuronal activation led to elevated miR-184–3p in neuron-derived exosomes that were taken up by GSCs and reduced the mRNA N6-methyladenosine (m6A) levels by inhibiting RBM15 expression. RBM15 deficiency decreased m6A modification of DLG3 mRNA and subsequently induced GSC PMT by activating the STAT3 pathway. Loss of miR-184–3p in cortical neurons reduced GSC xenograft growth, even when neurons were activated. Levetiracetam, an antiepileptic drug, reduced the neuronal production of miR-184–3p-enriched exosomes, inhibited GSC PMT, and increased radiosensitivity of tumors to prolong survival in xenograft mouse models. Together, these findings indicate that exosomes derived from active neurons promote GBM progression and radioresistance by inducing PMT of GSCs. Significance: Active neurons secrete exosomes enriched with miR-184–3p that promote glioblastoma progression and radioresistance by driving the proneural-to-mesenchymal transition in glioma stem cells, which can be reversed by antiseizure medication levetiracetam.
The Chromatin Remodeler CHD4 Sustains Ewing Sarcoma Cell Survival by Controlling Global Chromatin Architecture
Authors: Joana Graca Marques, Blaz Pavlovic, Quy A. Ngo, Gloria Pedot, Michaela Roemmele, Larissa Volken, Samanta Kisele, Romain Perbet, Marco Wachtel, Beat W. Schäfer
Journal: Cancer Research (2023)

Abstract Ewing sarcoma is an aggressive cancer with a defective response to DNA damage leading to an enhanced sensitivity to genotoxic agents. Mechanistically, Ewing sarcoma is driven by the fusion transcription factor EWS-FLI1, which reprograms the tumor cell epigenome. The nucleosome remodeling and deacetylase (NuRD) complex is an important regulator of chromatin function, controlling both gene expression and DNA damage repair, and has been associated with EWS-FLI1 activity. Here, a NuRD-focused CRISPR/Cas9 inactivation screen identified the helicase CHD4 as essential for Ewing sarcoma cell proliferation. CHD4 silencing induced tumor cell death by apoptosis and abolished colony formation. Although CHD4 and NuRD colocalized with EWS-FLI1 at enhancers and super-enhancers, CHD4 promoted Ewing sarcoma cell survival not by modulating EWS-FLI1 activity and its oncogenic gene expression program but by regulating chromatin structure. CHD4 depletion led to a global increase in DNA accessibility and induction of spontaneous DNA damage, resulting in an increased susceptibility to DNA-damaging agents. CHD4 loss delayed tumor growth in vivo, increased overall survival, and combination with PARP inhibition by olaparib treatment further suppressed tumor growth. Collectively, these findings highlight the NuRD subunit CHD4 as a therapeutic target in Ewing sarcoma that can potentiate the antitumor activity of genotoxic agents. Significance: CRISPR/Cas9 screening in Ewing sarcoma identifies a dependency on CHD4, which is crucial for the maintenance of chromatin architecture to suppress DNA damage and a promising therapeutic target for DNA damage repair-deficient malignancies.
Deep learning enables spatial mapping of the mosaic microenvironment of myeloma bone marrow trephine biopsies
Authors: Yeman Brhane Hagos, Catherine S.Y. Lecat, Dominic Patel, Anna Mikolajczak, Simon P. Castillo, Emma J. Lyon, Kane Foster, Thien-An Tran, Lydia S.H. Lee, Manuel Rodriguez-Justo, Kwee L. Yong, Yinyin Yuan
Journal: Cancer Research (2023)

Bone marrow trephine biopsy is crucial for the diagnosis of multiple myeloma. However, the complexity of bone marrow cellular, morphologic, and spatial architecture preserved in trephine samples hinders comprehensive evaluation. To dissect the diverse cellular communities and mosaic tissue habitats, we developed a superpixel-inspired deep learning method (MoSaicNet) that adapts to complex tissue architectures and a cell imbalance aware deep learning pipeline (AwareNet) to enable accurate detection and classification of rare cell types in multiplex immunohistochemistry images. MoSaicNet and AwareNet achieved an AUC of >0.98 for tissue and cellular classification on separate test datasets. Application of MoSaicNet and AwareNet enabled investigation of bone heterogeneity and thickness as well as spatial histology analysis of bone marrow trephine samples from monoclonal gammopathies of undetermined significance (MGUS) and from paired newly diagnosed and posttreatment multiple myeloma. The most significant difference between MGUS and newly diagnosed multiple myeloma (NDMM) samples was not related to cell density but to spatial heterogeneity, with reduced spatial proximity of BLIMP1+ tumor cells to CD8+ cells in MGUS compared with NDMM samples. Following treatment of patients with multiple myeloma, there was a reduction in the density of BLIMP1+ tumor cells, effector CD8+ T cells, and regulatory T cells, indicative of an altered immune microenvironment. Finally, bone heterogeneity decreased following treatment of patients with multiple myeloma. In summary, deep learning-based spatial mapping of bone marrow trephine biopsies can provide insights into the cellular topography of the myeloma marrow microenvironment and complement aspirate-based techniques.
A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better
Authors: Dijana Djureinovic, Sarah A. Weiss, Irina Krykbaeva, Rihao Qu, Ioannis Vathiotis, Myrto Moutafi, Lin Zhang, Ana L. Perdigoto, Wei Wei, Gail Anderson, William Damsky, Michael Hurwitz, Barbara Johnson, David Schoenfeld, Amit Mahajan, Frank Hsu, Kathryn Miller-Jensen, Yuval Kluger, Mario Sznol, Susan M. Kaech, Marcus Bosenberg, Lucia B. Jilaveanu, Harriet M. Kluger
Journal: Molecular Cancer (2023)

Abstract Background Stimulating inflammatory tumor associated macrophages can overcome resistance to PD-(L)1 blockade. We previously conducted a phase I trial of cabiralizumab (anti-CSF1R), sotigalimab (CD40-agonist) and nivolumab. Our current purpose was to study the activity and cellular effects of this three-drug regimen in anti-PD-1-resistant melanoma. Methods We employed a Simon’s two-stage design and analyzed circulating immune cells from patients treated with this regimen for treatment-related changes. We assessed various dose levels of anti-CSF1R in murine melanoma models and studied the cellular and molecular effects. Results Thirteen patients were enrolled in the first stage. We observed one (7.7%) confirmed and one (7.7%) unconfirmed partial response, 5 patients had stable disease (38.5%) and 6 disease progression (42.6%). We elected not to proceed to the second stage. CyTOF analysis revealed a reduction in non-classical monocytes. Patients with prolonged stable disease or partial response who remained on study for longer had increased markers of antigen presentation after treatment compared to patients whose disease progressed rapidly. In a murine model, higher anti-CSF1R doses resulted in increased tumor growth and worse survival. Using single-cell RNA-sequencing, we identified a suppressive monocyte/macrophage population in murine tumors exposed to higher doses. Conclusions Higher anti-CSF1R doses are inferior to lower doses in a preclinical model, inducing a suppressive macrophage population, and potentially explaining the disappointing results observed in patients. While it is impossible to directly infer human doses from murine studies, careful intra-species evaluation can provide important insight. Cabiralizumab dose optimization is necessary for this patient population with limited treatment options. Trial registration ClinicalTrials.gov Identifier: NCT03502330.
The epidemiology of acne vulgaris in a multiethnic adolescent population from Rotterdam, the Netherlands: A cross-sectional study
Authors: Willemijn C.A.M. Witkam, Susi E. Dal Belo, Sayeh Pourhamidi, Edouard Raynaud, Magali Moreau, Luc Aguilar, Pauline W. Jansen, Tamar E.C. Nijsten, Luba M. Pardo
Journal: Journal of the American Academy of Dermatology (2023)

Although acne is a prevalent multifactorial inflammatory skin condition, few studies were performed in multiethnic populations.